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Trial #NCT01790295
Primary Myelofibrosis Clinical Trials

Ruxolitinib Prior to Transplant in Patients With Myelofibrosis


Exploring the Potential of Dual Kinase JAK 1/2 Inhibitor Ruxolitinib (INC424) With Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis
Study ID: GCO 12-1809; Secondary ID: MPD-RC 114; Source: Mount Sinai School of Medicine
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Definitions
Interventional trials
Determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments.
Observational trials
Address health issues in large groups of people or populations in natural settings.
Recruiting
Participants are currently being recruited and enrolled.
Active, not recruiting
Study is ongoing (i.e., patients are being treated or examined), but enrollment has completed.
Not yet recruiting
Participants are not yet being recruited or enrolled.
Enrolling by invitation
Participants are being (or will be) selected from a predetermined population.
Completed
The study has concluded normally; participants are no longer being examined or treated (i.e., last patient's last visit has occurred).
Withdrawn
Study halted prematurely, prior to enrollment of first participant.
Suspended
Recruiting or enrolling participants has halted prematurely but potentially will resume.
Terminated
Recruiting or enrolling participants has halted prematurely and will not resume; participants are no longer being examined or treated.
Status Recruiting
Country Multiple Countries
Study type Interventional
Enrollment 86
Start date February 2013
Completion date February 2021
Phase Phase 2
Sponsor Mount Sinai School of Medicine
Summary:
The purpose of this study is to find out if giving the study drug Ruxolitinib (INC424) prior
to a combination of other chemotherapeutic drugs (Fludarabine and Busulfan) before infusing
another person's hematopoietic stem cells (bone marrow transplantation) will be successful
in people who have advanced primary myelofibrosis (PMF), post-polycythemia vera
myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF),
collectively known as myelofibrosis (MF). MF is a disorder in which bone marrow tissue
develops in abnormal sites because the bone marrow itself undergoes fibrosis or scarring.
This study plans to evaluate whether adding the drug Ruxolitinib will further aid in
reducing pre-transplant spleen size, improve physical performance levels and reduce adverse
events (side effects) related to the transplant. Ruxolitinib is a drug that is approved by
the FDA for the treatment of patients with advanced forms of myelofibrosis. Using
Ruxolitinib prior to stem cell transplantation is experimental.
Description:
A two- stage Simon Phase II study will be conducted in each of two groups of patients:
related and unrelated donor transplants. In each donor transplant group, the first stage of
this design will include 11 patients evaluated for death or graft failure by 100 days
post-transplant. In each stratum, we will enroll additional patients (up to 20%) of stratum
total to take into account exclusions due to donor failure (such as donor deemed unsuitable
for stem cell donation due to medical or other reasons) only. Those patients who have
toxicities related to Ruxolitinib and not been able to reach HCT due to these toxicities
will be included in the estimation of overall failure rates. Only those patients who are
excluded based on donor related issues without any regimen related complications will be
excluded from the estimation of failure rates. However, all data on these patients will be
reported.
Eligibility:
Gender: Both
Age: 18 Years - 70 Years
Inclusion Criteria:
- Documented diagnosis of primary myelofibrosis according to WHO criteria or post PV myelofibrosis or post ET myelofibrosis as per IWG-MRT criteria
- Age 18-70 years
- Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria OR Intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely
1. Red cell transfusion dependency
2. Unfavorable Karyotype
3. Platelet count <100 x 109/l
- Blasts in the PB and BM =10% prior to study enrollment
- Availability of a suitable matched related (6/6 or 5/6) or unrelated donor (10/10 or 9/10 antigen or allele matched).
- Able to give informed written consent
- ECOG Performance status of 0-2.
- Life expectancy >3 months
- Off all MF-directed therapy including investigational agents for at least 2 weeks prior to study enrollment and recovered from all toxicities*
- Adequate organ function
- Adequate renal function - creatinine <1.5 x IULN
- Adequate hepatic function - AST/ALT <2.5 x IULN, Total Bilirubin <1.5 x IULN
- Adequate hematopoietic function - Platelet =50 x 109/l and ANC =1.0 x 109/l
- LVEF >40% (MUGA or echocardiogram) Normal per Institutional standard
- Adequate pulmonary function with DLCO >50%
- A patient who has been on stable dose of Ruxolitinib and has received ruxolitinib =6 months prior to the study entry will be considered potentially eligible for the study with the caveat that there is no evidence of loss of response (>5cm increase in spleen size from the nadir).
Exclusion Criteria:
- Any previous JAK2 inhibitor treatment prior to study enrollment, with the exception of Ruxolitinib
- Hypersensitivity to JAK inhibitor
- Clinical or laboratory evidence of cirrhosis
- Prior allogeneic transplant for any hematopoietic disorder
- >20% blast in the PB or BM prior to HCT or had leukemic transformation (>20% blasts in PB or BM any time prior to HCT)
- Syngeneic donor
- Cord Blood transplant
- Active uncontrolled infection
- H/o another malignancy within 5-years of date of HCT except h/o basal cell or squamous cell carcinoma of skin or PV or ET
- Known HIV positive
- Pregnancy at the time of BMT
- Any other concurrent illness which in investigator's opinion puts the patient at excessive risk of treatment related toxicities
- Unable to give informed consent
- Active infection with hepatitis A,B or C virus
- Subjects who require therapy with a strong CYP3A4 inhibitor prior to enrollment to this study
Outcome:
Primary outcome
  • Assessment of 100-day survival without graft failure
    To determine the feasibility of combining Ruxolitinib (INC424) with a RIC regimen likely to produce success post transplantation, success being defined as patient being alive, and without graft failure at day 100-post allogeneic stem cell transplantation (in patients who receive (a) related donor transplant and in those who receive (b) an unrelated donor transplant.
    Time frame: Day 100-post allogeneic stem cell transplantation
Secondary outcome
  • Acute and chronic GvHD
    Time frame: 1-year post transplant
  • Association of cytokines levels with acute and chronic GvHD
    Time frame: 30 days post transplant
  • Association of cytokines levels with acute and chronic GvHD
    Time frame: 100 days post transplant
  • Chimerism studies
    Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment
    Time frame: 30 days post transplant
  • Chimerism studies
    Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment
    Time frame: 60 days post transplant
  • Chimerism studies
    Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment
    Time frame: 100 days post transplant
  • Expression profiling and measurements of cytokines prior to start of Ruxolitinib, prior to start of chemotherapy for conditioning
    Time frame: 30 days post transplant
  • Expression profiling and measurements of cytokines prior to start of Ruxolitinib, prior to start of chemotherapy for conditioning
    Time frame: 100 days post transplant
  • Impact of allogeneic stem cell transplant on myelofibrosis associated symptoms and overall quality of life
    Time frame: up to 48 months
  • Neutrophil recovery
    Neutrophil recovery will be defined as first of the three consecutive days with neutrophil count =0.5 x 109/l.
    Time frame: up to 4 years
  • Non-relapse mortality (NRM)
    NRM will be defined as death in first 30 days due to any cause, and subsequently death due to any cause without the recurrence or progression of myelofibrosis. Cumulative incidence of NRM will be calculated taking relapse/progression as competing event.
    Time frame: 100 days
  • Non-relapse mortality (NRM)
    NRM will be defined as death in first 30 days due to any cause, and subsequently death due to any cause without the recurrence or progression of myelofibrosis. Cumulative incidence of NRM will be calculated taking relapse/progression as competing event.
    Time frame: 1-year post transplant
  • Overall Survival
    Time frame: 1-year post transplant
  • platelet recovery
    Platelet recovery will be defined as first of the 7 days with platelet count =20 x 109/l, without platelet transfusion support and both maintained for 30 days without transfusion support or myeloid cytokine support.
    Time frame: up to 4 years
  • Progression-free survival
    Time frame: 1-year post transplant
  • Relapse/progression (defined as per IWG-MRT criteria)
    Time frame: 1-year post transplant
  • Remission status according to IWG-MRT criteria
    Time frame: Day 100 post transplant
  • Remission status according to IWG-MRT criteria
    Time frame: 6 months post transplant
  • Remission status according to IWG-MRT criteria
    Time frame: 12 months post transplant
Contacts:
  • Adam Mead, MD; University of Oxford, John Radcliffe Hospital (Study Chair)
  • John Mascarenhas, MD; Mount Sinai School of Medicine (Principal Investigator)
  • Vikas Gupta, MD, FRCP, FRCPath; University of Toronto (Study Chair)
Location Country Status
Mayo Clinic Scottsdale, Arizona United States Recruiting
Emory Hospital Atlanta, Georgia United States Recruiting
University of Illinois at Chicago Chicago, Illinois United States Recruiting
University of Maryland Baltimore, Maryland United States Recruiting
Icahn School of Medicine at Mount Sinai New York, New York United States Recruiting
Weill CornellMedical College New York, New York United States Not yet recruiting
Wake Forest Baptist Medical Center Winston-Salem, North Carolina United States Recruiting
Ohio State University Columbus, Ohio United States Recruiting
University of Utah Salt Lake City, Utah United States Not yet recruiting
Princess Margaret Cancer Centre, University of Toronto Toronto, Canada Recruiting
Chaim Sheba Medical Center Ramat Gan, Israel Not yet recruiting
University of Florence Florence, Italy Not yet recruiting
University of Oxford Oxford, United Kingdom Not yet recruiting
Sponsors:
  • John Mascarenhas - (Lead Sponsor)
  • Myeloproliferative Disorders-Research Consortium - Collaborator
  • National Cancer Institute (NCI) - Collaborator
  • Incyte Corporation - Collaborator
  • Novartis - Collaborator

Related trials: Terms
  • Stem cell transplant
  • Myelofibrosis
  • Ruxolitinib
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